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Hereditary Breast Cancer

Women newly diagnosed with breast cancer often fear their daughter is doomed to have breast cancer as well. These women’s sisters may also start to panic.

It is true that women who have a mother or sister with breast cancer are at increased risk. But having an increased risk does not make cancer inevitable. In fact, most women with a mother or sister with breast cancer will never be diagnosed themselves.

Approximately 11% of women with breast cancer have a family member with the disease. Some of these women carry a BRCA mutation, but most do not. Why these other families are at higher risk is not yet understood.There are probably other inherited genetic mutations that we haven't yet discovered that increase breast cancer risk. It is also possible that there are specific traits or environmental exposures shared by family members that can increase breast cancer risk.

Having a family history of breast cancer does not mean that you will develop breast cancer

Having a family history of breast cancer does not mean that you will develop breast cancer. But it does mean that you are at increased risk. Having one first-degree relative (mother, sister, or daughter) with breast cancer approximately doubles a woman’s risk. Think of it this way: In a group of 100 women who do not have a family history of breast cancer, 5 would be expected to go on to develop breast cancer. In contrast, in a group of 100 women with one first-degree relative who has the disease, 10 would be expected to go on to develop breast cancer. Having two first-degree relatives increases a woman’s risk five-fold. This means that in a group of 100 women with two first-degree relatives with breast cancer, 25 would be expected to go on to develop breast cancer.

Most breast cancers are sporadic— the women with the disease are unlikely to have inherited their risk. Only five to ten percent of women with breast cancer have a dominant cancer gene that is passed on to succeeding generations from either the father or the mother. This type of breast cancer is what we refer to as hereditary breast cancer. The most common inherited mutations are BRCA1 and BRCA2.

Why doesn’t everyone with a BRCA genetic mutation get breast cancer? The word scientists use to explain this variability is penetrance. Whether or not the mutation in the gene results in cancer depends on whether that mutation has an effect. Some people with a BRCA mutation probably won’t get cancer unless there is an additional genetic alteration that occurs. Or they may have inherited other genes that protect them from having a cancer develop.

Founder’s Mutations

There are over 700 possible mutations in each of the BRCA genes, just as the same word can be mistyped in a number of different ways. Three of these mutations were found consistently in women of Ashkenazi (Eastern European Jewish) descent. The mutations are 185delAG, 5382InsC, and 6174delT. These are often called founder mutations because they’re more common in small tightly knit populations. The founder is the first person who ever got the mutated gene, inadvertently “founding” it and then passing it down to her or his descendants. Intermarriage perpetuates the gene through many generations. Since one of the three founder mutations is present in 2.5 percent of Ashkenazi Jews, this group has been studied extensively.

Founder genes are not exclusive to Ashkenazi Jews. When researchers started looking at other populations, they found similar situations. In Iceland, where there’s a lot of intermarriage, there is also a predominant mutation of BRCA2. (Only nine percent of people in Iceland with a mutated BRCA gene have a BRCA1 mutation, while 54% have BRCA2.) In Norway, which mutation a person gets depends on which fjord she lives on. And a study of Hispanic women living in Los Angeles found that six mutations were responsible for 47% of the positive genetic tests, with four of the six seeming to be almost exclusive to families with Latin American/Caribbean or Spanish ancestry.

All of this is important when it comes to testing. If you’re from an Ashkenazi family and have breast or ovarian cancer, instead of looking for any of the thousands of possible mutations, doctors focus on the three common mutations—and the gene is much easier to test. Investigators have shown that if a Jewish woman does not carry one of those three founder mutations it is highly unlikely that a different mutation will be found. On the other hand, if testing for a mutation means studying the whole paragraph to find the typo, it’s more time-consuming, and thus more expensive, to test.

Other Known Mutations

Other genetic mutations that moderately increase breast cancer risk include TP53, PTEN, STK11 and CDH1. TP53, which sometimes goes under the name Li-Fraumeni Syndrome after the scientists who discovered it, causes significant problems including childhood malignancies, sarcomas, brain tumors, leukemia, adrenocortical tumors, and colon cancer. PTEN, which is also called Cowden syndrome, can show up in childhood. It also increases risk for endometrial, thyroid, kidney, colon, and skin cancers. Families with a lot of different cancers including breast might be more likely to have a syndrome like this.

Another syndrome often called Peutz-Jeghers syndrome(STK11) sometimes manifests with lip freckling. In addition to breast cancer, it increases risk for colorectal, small bowel, pancreatic, and ovarian cancers. Finally hereditary diffuse gastric cancer (HDGC) or CDH1 can show up in the breast as lobular cancer, in addition to causing stomach cancer.

Some of the other genes that have been identified include CHEK2, ATM, BRIP, BARD, and PALB2. The CHEK2 mutation is found in Europeans of Northern and Eastern European descent. It is also involved in DNA repair and women who carry the mutation have a two-to-three times increased risk of developing breast cancer. This means if the average risk is one percent per year theirs is two to three percent per year. PALB2 which stands for partner and localizer of BRCA2, was initially thought to be a moderate risk mutatio, but a study in 2014 found the lifetime risk to be equivalent to BRCA2, with the risk highest among individuals younger than 40.